Hischsprung disease (HSCR) is an intestinal disorder with strong genetic components. RET was considered as the strongest contributor. Multiple single nucleotide polymorphisms (SNP) were demonstrated as associated with HSCR in different populations. However, whether the associations of reported SNPs derived from one causal variants or congregations of multiple variants were still not clear. In this study, we successfully genotyped 16 SNPs in RET with a largest case-control study to date, totaling 1470 HSCR and 1473 control subjects in South Chinese population. Multiple independent contributors were identified through pairwise and stepwise logistic regression. The intragenic synergistic effect among these SNPs were further explored and cross validated by logistic regression and multifactor dimensionality reduction (MDR). Noteworthy, in further subclinical manifestation analysis, the six potential independent contributors in RET were more essential for the patients with short-segment aganglionosis (S-HSCR). Although functional evaluations are required, our comprehensive analysis for RET gene integrating detailed disease subphenotypes might facilitate improved understanding for the genetic understanding of HSCR etiology.